This invention includes various medical devices and systems for use in surgical and interventional procedures. More particularly, the invention relates to devices and systems for the delivery and injection of therapeutic and diagnostic agents, solutions or injectates into bodily tissue, bodily substances or synthetic materials attached to bodily tissue, such as an artificial graft. Additionally, the invention relates to methods of delivering and injecting a solution at a target site within the body for the treatment or diagnosis of that target site.
Despite the continual advances in medical technology, particularly in the treatment of heart disease, vascular disease, cancer, pain, allergies, orthopedic repair and many other diseases and conditions, there are a significant number of patients for whom conventional surgical and interventional therapies are not feasible or are insufficient to treat the disease or condition. For many patients, medical treatment with drugs and the like is the only feasible treatment available.
There have been many recent advances in drug therapies, particularly with regard to cell or site-specific therapeutics (as opposed to systemic therapeutics) such as pharmacologic agents (e.g., anesthetics and analgesics) and biologic agents (e.g., genetically engineered material). Unlike the systemic administration of therapeutics, typically taken orally or given intravenously, much of the effectiveness of cell- or site-specific therapeutics is based on the ability to accurately and precisely deliver the therapeutics to the targeted site within the body.
Needle injection devices are the most commonly used means for the site-specific administration of agents or solutions. Although there have been advances in needle-based drug delivery/injection systems, these systems have significant shortcomings and disadvantages. These shortcomings and disadvantages are exemplified, for example, in gene therapy applicationsxe2x80x94the implantation of genetic material or engineered cells in specific targets in the human anatomy to create a therapeutic or preventative effect.
Depending on the disease being treated, gene therapy can be angiogenic or anti-angiogenic. The intended result of angiogenic therapy is the promotion of angiogensisxe2x80x94a complex biological process that results in the growth of new blood vessels. Angiogenic therapy has been used experimentally for treating, for example, cardiac ischemia, coronary artery disease (e.g., atherosclerosis), and ischemia in peripheral vascular beds. Conversely, anti-angiogenic therapy involves the reduction in the proliferation of blood vessels, for example, to cut-off the supply of blood to a tumor or to proliferating pannus-type tissue, and to inhibit the abnormal growth of retinal vessels that leads to blindness.
An important factor in achieving the desired result of gene therapy is direct exposure of the genetic material to a specific target site for a sustained period of time. This is particularly challenging for gene therapies that require delivering genetic material to the nuclei of cells. Depending on the location of the targeted tissue and the type of condition being treated, exposure of the genetic material to the target site may involve direct approaches, such as an open or less invasive surgical approach, or endovascular approaches by means of a catheter. With any approach, there are significant challenges in the delivery of genetic material to the appropriate cells of the patient in a way that is specifically targeted, efficient and safe.
For optimum xe2x80x9cup regulationxe2x80x9d of the gene therapy agent, the agent must undergo some atomization in order to be effectively perfused within the target site. If the gene therapy drug is not sufficiently atomized (i.e., broken up into very small micro-particles), dispersion and then absorption of the drug may be greatly reduced, resulting in minimal to no positive affect on the patient. Needle-based syringes are not capable of such atomization and, instead, deliver the injectate in the form of a bolus, which is less likely to be effectively dispersed and absorbed within tissue.
Moreover, in certain applications of gene therapy, it is important to minimize the systemic exposure of the gene therapy agent in order to avoid unwanted side-affects. The use of a needle or other penetrating means to inject the targeted tissue area unavoidably involves making a hole into the target site. This results in much of the injectate leaking back out of the hole, and being released systemically throughout the body or being wasted. This also results in increased treatment costs and requires more injections, time and agent to achieve the desired affect.
Gene therapy has been used, for example, to create angiogenesis in hypoxic (i.e., oxygen-deprived) heart tissue. In a cardiac surgical procedure, the angiogenic solution is typically delivered by making a number of syringe injections, typically in a grid-like pattern, directly though the epicardium (i.e., the outer surface of the heart) at the ischemic portion of the myocardium. An equivalent endocardial approach (i.e., through the inside surface of the heart) involves delivering a catheter employing a distal needle within a ventricular chamber and injecting the angiogenic solution through the endocardium to the myocardium. The intent of both approaches is to cause the cells in the target tissue to express the desired growth factor protein continuously for a desired time period. Other means of delivering cardiac angiogenesis agents include injecting the agent within the pericardial sac (i.e., intrapericardial), within the coronary arteries (i.e., intracoronary) or directly into the myocardium (i.e., the middle layer of the heart wall).
Although some recent clinical studies have suggested that there is some marginal resulting angiogenic response with syringe/needle-based injection, there are definite disadvantages of employing a syringe/needle-based injector or other tissue-penetrating device. For example, myocardial ischemia typically involves an affected surface area in the range of approximately 3 mm2 to 10 mm2. A single needle injection in ischemic tissue can only provide a solution dispersion in a much smaller area defined by the size of the needle and the limited ability of the agent to diffuse through the tissue. Thus, multiple needle-based injections may be required in order to sufficiently disperse the solution over the entire affected area. As the number of injections increases, the procedure time is increased and a greater volume of the gene therapy agent is required to effectively treat the ischemic area. More time and greater drug volume increase the cost of the procedure.
Furthermore, it is known that needle injections or penetration into the tissue can traumatize or destroy tissue cells and, as a result, increase a patient""s risk of post-operative arrhythmia. This is particularly due to the difficulty in precisely controlling the penetration of the needle during injection. The more injections or penetrations, the greater the cell destruction and risk of arrhythmia. Still another disadvantage of multiple needle-based injections of growth factor is the need to carefully track the location of each injection site so as to prevent the accidental delivery of growth factor to non-diseased tissue.
There are some gene therapies that do not involve needle-based drug delivery. Instead, indwelling catheters and drug-infused stents have been used for releasing the therapeutic agent in a steady, controlled-release fashion. These approaches present a greater risk of releasing the agent systemically. Additionally, it is more difficult to assess the actual dosing of the target area that takes place. Thus, these approaches have the disadvantages of being less effective, not as safe, and more costly than injections.
Another condition in which site-specific or local drug delivery is commonly employed is in the treatment of peripheral vascular disease (such as deep vein thrombosis and embolisms). One such treatment is venous lytic therapy, the dissolving of blood clots (thrombus) in the peripheral vasculature (e.g., femoral and illiac arteries and veins). Lytic therapy involves systemically infusing thrombolytics, such as urokinase, streptokinase, reteplase and tPA. Other more recently developed procedures involve directly delivering the thrombolytics into the thrombus site through the use of indwelling infusion catheters. In order to effectively lyse the thrombus, the thrombolytics are typically infused for many hours, even as much as a day or more, increasing the necessary length of hospital stay and the overall cost of the procedure.
Still another area in which the localized delivery of therapeutics is indispensable is in the treatment of arterial-venous (AV) access routes for renal dialysis. There are several ways in which AV access is established. One is by means of an AV graft, a tube made of a synthetic material such as teflon (e.g., PTFE), which is implanted to connect an artery and vein in the arm, for example. The graft takes approximately two weeks to mature and should be placed at least a few weeks before use for hemodialysis. Unfortunately, these grafts are prone to stenosis and the spreading of infection, and typically only survive for not more than about xc2xd years. Another type of AV access route is an AV fistula. This is a surgical connection made between an artery and a vein. The fistula, once surgically placed, takes around twelve weeks to mature, and thus must be placed several months before hemodialysis is anticipated. Although the infection and stenosis rate of fistulas is far less than that of AV grafts, infection and stenosis are not uncommon.
Double lumen catheters are another type of AV access means. The may be used for long-term or temporary applications. Those used long term are surgically placed in a tunneling fashion under the skin. AV access catheters are typically placed into either the subclavian or jugular vein. Occasionally, they are temporarily placed in the femoral vein. Short-term AV access catheters are generally placed when dialysis is needed emergentlyxe2x80x94either when the referral of the patient to dialysis is unduly delayed, or when a permanent AV access fails and the patient is too unstable to have it revised until after an emergency treatment. AV access catheters may develop serious infections, or may thrombose, ultimately leading to failure of the device. Moreover, the veins they are placed in are prone to clotting.
Conventional treatments for problems (e.g., stenosis, infection and thrombus formation) that may arise with AV access grafts, fistulas or catheters typically involve surgical intervention, including the repair or replacement of the AV access device, the physical removal of stenotic plaque and the chemical or physical removal of blood clots. Clearly the elimination of any surgical procedure is advantageous to reducing morbidity and pain. Thus, there is still a need for an improved means and method for treating and preventing conditions related to the use of AV access devices.
The disadvantages of conventional drug delivery systems also exist in the treatment of other conditions such neurovascular disease, cancer, rheumatoid arthritis, etc. Accordingly, there is a need for devices and methodologies for delivering drugs and other solutions to bodily tissue which are more precise, efficient, and effective, and less costly than conventional devices and methods. Additionally, it is highly desirable to have devices and methods for delivering solutions to bodily tissue that are safer and less invasive than current devices and methods. There is also a need for medical agent delivery devices that are packaged and supplied in ways that make their use convenient and easy for self-application and institutional use. Thus, there still exists a need for enabling technology for the more effective and safe local delivery of therapeutic agents.
The present invention includes novel means and methods for delivering and injecting a solution or agent into a target site within the body for the purpose of treating or diagnosing the target site. The target site may be an area of tissue or a substance affixed or adjacent to the tissue area or its cells. More specifically, the target site may be an organ, a body lumen, a vessel lumen, a solid tumor, a synthetic graft, plaque, thrombus, etc.
The devices of the present invention include injection systems and components for accurately and precisely delivering, injecting and perfusing a therapeutic or diagnostic agent, preferably in a fluid form, directly into the target site without the need to penetrate the tissue with anything other than the agent itself. More specifically, none of the embodiments employ a needle or other penetrating device for creating a space within which the agent is injected.
The injection systems of the present invention include embodiments for use in intraoperative and interventional clinical settings as well as in certain non-clinical settings in which the patient injects himself or herself. More specifically, they are configured for delivering a solution from an ampule and injecting it into a target site within the body or within an artificial graft affixed to the body through either a surgical opening, a less invasive surgical opening (such as through a trocar port), or endovascularly.
Generally, the injection systems comprise, at least in part, a propulsion apparatus, an ampule reservoir, often called a syringe or ampule, for receiving and holding the solution or agent, and a dispersion means distal to the ampule for transporting the solution or agent from the reservoir to the target site and for perfusing or dispersing it within the target site.
The propulsion devices of the present invention produce pressures great enough to inject a solution or agent within the target site without the need for a needle or any other penetrating device. These devices may be powered by any appropriate propulsion mechanism or energy, such as a spring-loaded member or a self-contained inert gas (such as a cartridge containing carbon dioxide, nitrogen, argon, etc.) for ejecting or propelling an agent out of a reservoir. The propulsion apparatus is operatively coupled to the reservoir and is used to propel the agent out of the reservoir at a desired pressure such as in the range from about 1800 psi to about 2300 psi. The propulsion devices of the present invention further comprises means for selecting the volume of agent to be propelled from the reservoir as well as means for selecting a pressure at which the agent is propelled from the reservoir. Preferably, the propulsion devices are ergonomically configured to be held and actuated by one hand of the user.
The ampule reservoirs of the present invention are intended to hold at least one dose, but may, however, have any appropriate volume for containing any appropriate dose of solution. The ampule may be reusable or disposable after a single use. The ampule sits within the housing of the propulsion device with its distal end in sealed engagement with the dispersion means and its proximal end in operative engagement with a piston which forces the agent out of the reservoir upon activation of the propulsion device. Alternately, the ampule may be modular form which can be releasably coupled to the dispersion means to form a nozzle assembly which is attachable to the propulsion device. The ampule may come pre-filled from the supplier or may be refillable by the physician.
The ampule reservoir and dispersions means of the present invention each have at least one orifice through which the agent can pass through as it is propelled. The dispersion orifice(s) most preferably has a diameter in the range from about 0.1 mm to about 0.3 mm. The dispersion means is comprised of material(s) that are capable of withstanding the forces of the pressurized fluid to the extent that the pressure of the agent is substantially maintained as it passes through the dispersion means.
The most significant difference between the injection devices for use in surgical applications and those for use in interventional applications is their respective configurations of the dispersion means. In the surgical devices, the dispersion fixture is in the form of a fixture attached distally to the ampule reservoir. In the endovascular devices, it is in the form of a catheter assembly attached distally to the ampule reservoir. It follows that the means by which the respective dispersion means attach to the ampule reservoir are also different.
The various dispersion fixtures for use with the surgical devices, for both direct surgical and less-invasive surgical approaches, have an atraumatic surface which, when operatively positioned, faces the target site. The one or more dispersion orifices are located in this target-facing surface, which, for most of the surgical embodiments of the present invention, is smooth and substantially planar. The target-facing surface has a selected shape, size, and number and arrangement of dispersion orifices for defining a selected pattern of dispersion at the target site. The target-facing surface and/or the orifice arrangement may have a shape or configuration, for example, in the form of a circle, oval, ellipse, linear array, an annular array or an arched cone. In some less-invasive procedures, the dispersion means has a lower profile sufficient to be delivered through a less invasive opening. For some less-invasive devices of the present invention, the target-facing surface is not necessarily planar, but may be a rounded, tapered or flat tip of a cannula.
To enhance the precision and accuracy of dispersion of the agent through the dispersion orifices, a jewel having an orifice may be coaxially aligned on the proximal side of each dispersion orifice. The jewel is made of a very hard material such as stainless steel or a precious stone such as sapphire. The dispersion orifice(s) are in fluid communication with the reservoir orifice(s) by means of one or more pathways situated between them. In the surgical embodiments and some less-invasive embodiments of the present invention, each pathway is defined by a channel formed either within the dispersion fixture or within the distal end of the ampule. In other less-invasive embodiments, the pathway is the lumen of a tube, such as a cannula or other tubular piece. The tube may be malleable and steerable to facilitate delivery through a narrow, sometimes tortuous path to the target site. Additionally, these less-invasive embodiments may further comprise an endoscope.
The injection devices for use in interoperative or endovascular procedures employ a catheter as the means for dispersing the injectate into the target site. The catheters of the present invention are made of material(s) having physical properties sufficient to maintain the pressure of the injectate as it travels from the reservoir to the dispersion orifice. They each have a proximal end, a distal end having a distal tip, and a lumen there between. The distal tip has at least one dispersion orifice. The proximal end of the catheter is in sealed engagement with a distally tapering reservoir nozzle terminating in a reservoir orifice. The engagement is accomplished by means of a coupler mechanism, such as a leur fitting. A retainer means is then seated over the ampule reservoir to further ensure that the coupler mechanism is securely affixed to the ampule. Collectively, these components provide a sealed, fluid pathway from the reservoir to the catheter, and ensure the integrity of the pathway under pressurized conditions.
The preferred location of the catheter dispersion orifice(s) varies from embodiment to embodiment, depending on the intraoperative application at hand. Generally, the dispersion orifice(s) are located on the sidewall of the distal tip or at the distally facing end of the tip. Catheters having the dispersion orifice(s) within the sidewalls eject the agent laterally of the catheter tip and define an injection vector path that is substantially transverse or perpendicular to the longitudinal axis of the catheter. The dispersion orifices may be arranged in a circumferential pattern, a helical array, a number of linear arrays running parallel to the longitudinal axis of the catheter, or any other pattern that is suitable for the application. Catheters having the dispersion orifice(s) within the distally facing end of the catheter tip eject the agent distally of the catheter tip and define an injection vector path that is substantially coaxial or parallel to the longitudinal axis of the catheter.
The present invention further includes various surgical, less invasive surgical and endovascular methods for delivering and injecting a solution or agent to a target site within the body or within a graft affixed to the body without the need to penetrate the target site with other than the solution or agent itself. The present invention also includes methods for treating or diagnosing a target site within the body by means of a precisely delivered solution or agent. These methods may be standalone procedures or may be employed in the context of or as an adjunct to other intraoperative or interventional procedures and therapies. For example, a method of injecting a therapeutic agent into the heart may be performed in conjunction with a CABG surgery or a catheter-based, stent placement procedure.
The surgical and endovascular methods of the present invention include methods for injecting an agent into a target site within the body for the purpose of treating and/or diagnosing a target site or tissue adjacent a target site. Generally, these methods first involve accessing the target site within the body. The access site can be either a direct surgical opening, a less-invasive opening through which a port is placed, or a percutaneous opening through which a catheter is delivered. An ampule having a reservoir containing a volume of the therapeutic or diagnostic agent is provided. The volume of agent is then propelled from the reservoir at a selected pressure to a location proximate the target site. This involves exerting a force on the agent contained within the reservoir to provide the selected pressure. The selected pressure has a value such that the pressure of the agent as it makes contact with and disperses within the target site is sufficient to cause the agent to disperse within the target site without penetrating the target site with any other means. The agent is then dispersed into the target site in a substantially predefined pattern. When using a disposable ampule with a prefilled volume of agent, the ampule may be replaced with a second ampule containing a volume of the same or a different agent, and then repeating the remaining steps with the second ampule and any additional ampules necessary to complete the procedure.
As the physician deems appropriate, the step of positioning may involve either contacting a surface of the target site with the end effector or bringing it to within a selected distance from a surface of the target site. In the context of a surgical procedure, an end effector or dispersion means is delivered through the surgical opening and positioned proximate the target site. In a less-invasive surgical procedure, this involves delivering the end effector through a smaller opening such as a one made by a trocar port and steering the end effector towards the target tissue area. The less-invasive method may also involve the use of an endoscope to view some of the steps of the procedure. Similarly, in an endovascular procedure, a catheter is inserted into a percutaneous opening and the catheter tip is delivered proximate to the target site. The percutaneous opening may also be the external opening of an AV access graft.
The present invention also includes methods of diagnosing a target site. These methods generally involve percutaneously accessing the vasculature of a patient. A catheter having a non-penetrating catheter tip is provided and placed in fluid communication an ampule reservoir containing a volume of a diagnostic agent. The catheter is then inserted into the percutaneous access site, and its non-penetrating tip is then delivered proximate to the target site. A volume of the diagnostic injectate is then injected through the catheter and into the target site in a substantially predefined dispersion pattern at a pressure sufficient to cause the agent to disperse within the target site. The dispersion occurs without penetrating the target site with the catheter. Finally, the area proximate the target site is then viewed under fluoroscopy in order to determine the optimal location and tissue depth for injecting a therapeutic agent.
The invention is useful in the delivery and injection of precise, predetermined volumes of a therapeutic agents or solution directly to a target tissue site most commonly through a parenteral route. The more common parenteral routes and target sites are identified below in the following chart as well as agents commonly administered via these routes. It should be noted that this chart is intended to be illustrative only, and not intended to be a complete, comprehensive listing.
Various therapeutic applications in which the invention may be employed include but are not limited to the treatment of cardiac, cardiovascular, peripheral vascular, and neurovascular diseases, AV access graft stenosis and thrombus formation, cancer, rheumatoid arthritis, etc. More specific examples of the types of applications that can be accomplished by the present invention include, for example, the administration of angiogenic solutions to an ischemic area of myocardium, the delivery of a thrombolytic drug to a thrombus within a chamber of the heart or to the peripheral or neuro vasculature, administration of a solution to a portion of the atria contributing to atrial fibrillation, or the delivery of an anti-angiogenic solution to a solid tumor or through the vasculature supplying blood to a malignancy. Although only a few specific examples of target sites, delivery routes and therapeutic and diagnostic agents are specifically discussed here, any target site, any appropriate delivery route to a target site and any type of injectate may be delivered by the present invention. The injectates can include all classes of drugs, such as biological agents, pharmaceuticals and biopharmaceuticals, as well as solutions, such as saline and ethanol, which are not considered to be drugs. In addition to the primary function of delivering and dispersing the injectate, the catheters of the present invention may also perform adjunct functions, such as dilation of a vessel by means of an expandable member such as a balloon.